5
drug leads against established
classes of targets, its success rate
is much lower when it comes
to more challenging targets.
Even more troublesome are the
resulting false positives which
are a very undesireable outcome.
Additionally, the size of the
compound libraries mandating the
scale of the screening programs
is of concern — even at the
scale of millions of compounds,
calculations reveal that these
represent only a tiny fraction of the
possible lead candidates.
Fragment-based screening has
now become the method of
choice over HTS because fragment
libraries are easier to assemble,
maintain, and screen than HTS
libraries. And, it's clear that small
compounds or fragments (all
possible molecules of interest
below 500 Da
18
) not only cover a
larger chemical space, but bind
to more sites on more targets,
resulting in more hits.
Biophysics
provides the best
tools for finding hits
2
Sensitivity for detecting low affinities
Target
Identification
& Validation
HTS & Hit ID Hit Validation
Lead
Optimization
Drug
Development
Fragment-
based & small
molecule single-
dose screens
Validate hits
by ranking
affinities
Monitor K
d
during lead
optimization
Not all of the current techniques typically used in HTS can be applied to FBDD. Hit
detection in HTS is usually done with biochemical assays able to detect binding of
molecules in the micromolar range. Because of their smaller size (or fewer features),
